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Combination Strategies in Advanced CRC: E7208 and APOLLON

Insights from: Wells A. Messersmith, MD, FACP, University of Colorado Cancer Center
Published: Wednesday, Jun 20, 2018



Transcript: 

Wells A. Messersmith, MD, FACP: The E7208 trial basically asked the question of whether double biologics would be beneficial in the second-line setting. The history of double biologics in colorectal cancer is somewhat complicated. Approximately a decade ago, the BOND-2 trial and other studies suggested that there was a benefit to combining drugs that attack or block the VEGFR pathway and the EGFR pathway together, especially in the first-line setting in untreated patients. Although the small trials were promising, the large phase III randomized trial showed no benefit or even showed a trend of harm in some settings using a double biologic approach—double biologic meaning VEGFR and EGFR.

This study asked, could we perhaps resurrect that strategy in the second-line setting? Is it possible that giving cancer cells exposure to first-line therapy might change things such that they would be more sensitive in the second-line setting? And so, this trial looked at adding a VEGFR2 inhibitor, ramucirumab, and cetuximab to a very standard-of-care cytotoxic chemotherapy drug, irinotecan. This is a somewhat small trial of about 100 patients, so it certainly is not a trial that should change practice whatsoever. But nonetheless, there seemed to be a benefit toward the double-biologic approach versus the single-biologic approach. The implications of this trial are essentially hypothesis generation. Whether or not it will be followed up on with a larger trial that could be practice changing will remain to be seen. At this point, it doesn’t change practice; it’s just a very interesting study that could have follow-up studies.

The APOLLON study looked at whether or not you could use TAS-102, which is a new formulation of a 5-FU type of therapy—it’s not exactly like 5-FU, but it has a similar chemical composition—in combination with an EGFR inhibitor. I think we’ll probably see other studies looking at whether or not TAS-102 is superior to 5-FU when combined with oxaliplatin, TAS-OX, or when combined with irinotecan, TAS-IRI. In this trial, they looked at combining it with an EGFR inhibitor. The initial results look fairly promising. These 2 drugs seem to combine together. There weren’t any overly worrisome toxicity signals, and the efficacy signal seems to be there. It’s not practice changing in that this is not a very large trial. We’ll need to see other studies where TAS-102 is incorporated into these combination regimens, because currently, it’s approved just as a single agent after other therapies have been given. But so far, the data on combinations seem to be manageable. The drugs are basically recommended at their usual dose and schedules. And so, we’ll see whether or not it improves survival outcomes in larger studies.

Transcript Edited for Clarity 
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Transcript: 

Wells A. Messersmith, MD, FACP: The E7208 trial basically asked the question of whether double biologics would be beneficial in the second-line setting. The history of double biologics in colorectal cancer is somewhat complicated. Approximately a decade ago, the BOND-2 trial and other studies suggested that there was a benefit to combining drugs that attack or block the VEGFR pathway and the EGFR pathway together, especially in the first-line setting in untreated patients. Although the small trials were promising, the large phase III randomized trial showed no benefit or even showed a trend of harm in some settings using a double biologic approach—double biologic meaning VEGFR and EGFR.

This study asked, could we perhaps resurrect that strategy in the second-line setting? Is it possible that giving cancer cells exposure to first-line therapy might change things such that they would be more sensitive in the second-line setting? And so, this trial looked at adding a VEGFR2 inhibitor, ramucirumab, and cetuximab to a very standard-of-care cytotoxic chemotherapy drug, irinotecan. This is a somewhat small trial of about 100 patients, so it certainly is not a trial that should change practice whatsoever. But nonetheless, there seemed to be a benefit toward the double-biologic approach versus the single-biologic approach. The implications of this trial are essentially hypothesis generation. Whether or not it will be followed up on with a larger trial that could be practice changing will remain to be seen. At this point, it doesn’t change practice; it’s just a very interesting study that could have follow-up studies.

The APOLLON study looked at whether or not you could use TAS-102, which is a new formulation of a 5-FU type of therapy—it’s not exactly like 5-FU, but it has a similar chemical composition—in combination with an EGFR inhibitor. I think we’ll probably see other studies looking at whether or not TAS-102 is superior to 5-FU when combined with oxaliplatin, TAS-OX, or when combined with irinotecan, TAS-IRI. In this trial, they looked at combining it with an EGFR inhibitor. The initial results look fairly promising. These 2 drugs seem to combine together. There weren’t any overly worrisome toxicity signals, and the efficacy signal seems to be there. It’s not practice changing in that this is not a very large trial. We’ll need to see other studies where TAS-102 is incorporated into these combination regimens, because currently, it’s approved just as a single agent after other therapies have been given. But so far, the data on combinations seem to be manageable. The drugs are basically recommended at their usual dose and schedules. And so, we’ll see whether or not it improves survival outcomes in larger studies.

Transcript Edited for Clarity 
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